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Adrenal differentiation: a key role for the epigenetic factor EZH2

The adrenal gland produces glucocorticoid and mineralocorticoid hormones that are essential for life. This hormone production depends on a complex process of recruitment and differentiation of progenitor cells. Using a mouse model of gene ablation, the team “Molecular Pathophysiology of Adrenal & Endocrine Tissues” has shown that the epigenetic factor EZH2 is essential to allow differentiation of progenitor cells into cells capable of hormone synthesis. EZH2 ablation results in primary adrenal glucocorticoid deficiency, suggesting that EZH2 alterations may be involved in the aetiology of these potentially lethal diseases in patients.

In the normal adrenal (A), EZH2 deposits epigenetic marks on key genes of adrenal differentiation involved in the control of PKA signalling and development. This allows maintenance of the identity of steroidogenic cells that produce glucocorticoids. This also allows normal adrenal cortex renewal, starting from progenitor cells that first differentiate as zona glomerulosa and subsequently as zona fasciculata. In the absence of EZH2 (B), epigenetic marks are not deposited. Cells that normally produce glucocorticoids lose their identity. Furthermore, adrenal cell renewal is perturbed as differentiated cells dedifferentiate to a progenitor-like phenotype, reversing the normal flux of cells from progenitors to glomerulosa and fasciculata. This results in accumulation of aberrant progenitor-like cells. Altogether, mutant adrenals are not able to produce normal amounts of glucocorticoids, resulting in adrenal insufficiency.